title: Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection.
abstract: Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.
authors.affiliation: Departments of Nephrology and Endocrinology and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katagiri
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Koji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Kousuke
authors.initials: K
authors.lastname: Negishi
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D010880:Piperidines; D034741:RNA, Small Interfering; D018027:Receptors, Glucagon; D014688:Venoms; D014498:Uracil; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C520853:alogliptin; D002945:Cisplatin